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1.  Immature recent thymic emigrants are eliminated by complement1 
Recent thymic emigrants (RTEs) must undergo phenotypic and functional maturation to become long-lived mature naïve T cells. In CD4-cre NKAP conditional knockout mice, NKAP-deficient RTEs fail to complete T cell maturation. Here, we demonstrate that NKAP-deficient immature RTEs do not undergo apoptosis, but are eliminated by complement. C3, C4 and C1q are bound to NKAP-deficient peripheral T cells, demonstrating activation of the classical arm of the complement pathway. As thymocytes mature and exit to the periphery, they increase sialic acid incorporation into cell surface glycans. This is essential to peripheral lymphocyte survival, as stripping sialic acid with neuraminidase leads to the binding of natural IgM and complement fixation. NKAP-deficient T cells have a defect in sialylation on cell surface glycans, leading to IgM recruitment. We demonstrate that the defect in sialylation is due to aberrant α2,8-linked sialylation, and the expression of three genes (ST8sia1, ST8sia4 and ST8sia6) that mediate α2,8 sialylation are down regulated in NKAP-defcient RTEs. The maturation of peripheral NKAP-deficient T cells is partially rescued in a C3-deficient environment. Thus, sialylation during T cell maturation is critical to protect immature RTEs from complement in the periphery.
doi:10.4049/jimmunol.1401871
PMCID: PMC4332405  PMID: 25367120
2.  Historical development and current status of organ procurement from death-row prisoners in China 
BMC Medical Ethics  2015;16:85.
Background
In December 2014, China announced that only voluntarily donated organs from citizens would be used for transplantation after January 1, 2015. Many medical professionals worldwide believe that China has stopped using organs from death-row prisoners.
Discussion
In the present article, we briefly review the historical development of organ procurement from death-row prisoners in China and comprehensively analyze the social-political background and the legal basis of the announcement. The announcement was not accompanied by any change in organ sourcing legislations or regulations. As a fact, the use of prisoner organs remains legal in China. Even after January 2015, key Chinese transplant officials have repeatedly stated that death-row prisoners have the same right as regular citizens to “voluntarily donate” organs. This perpetuates an unethical organ procurement system in ongoing violation of international standards.
Conclusions
Organ sourcing from death-row prisoners has not stopped in China. The 2014 announcement refers to the intention to stop the use of organs illegally harvested without the consent of the prisoners. Prisoner organs procured with “consent” are now simply labelled as “voluntarily donations from citizens”. The semantic switch may whitewash sourcing from both death-row prisoners and prisoners of conscience. China can gain credibility only by enacting new legislation prohibiting use of prisoner organs and by making its organ sourcing system open to international inspections. Until international ethical standards are transparently met, sanctions should remain.
Electronic supplementary material
The online version of this article (doi:10.1186/s12910-015-0074-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12910-015-0074-0
PMCID: PMC4668660  PMID: 26630929
Organ sourcing; Prisoners; Medical ethics; China
3.  EPSA: A Novel Supercritical Fluid Chromatography Technique Enabling the Design of Permeable Cyclic Peptides 
ACS Medicinal Chemistry Letters  2014;5(10):1167-1172.
Most peptides are generally insufficiently permeable to be used as oral drugs. Designing peptides with improved permeability without reliable permeability monitoring is a challenge. We have developed a supercritical fluid chromatography technique for peptides, termed EPSA, which is shown here to enable improved permeability design. Through assessing the exposed polarity of a peptide, this technique can be used as a permeability surrogate.
doi:10.1021/ml500239m
PMCID: PMC4190640  PMID: 25313332
EPSA; cyclic peptides; permeability; polarity; intramolecular hydrogen bonding
4.  Outcome of Eyes Developing Retinal Detachment during the Early Treatment for ROP Study (ETROP) 
PURPOSE
To describe the structural and visual outcomes at age 6 years of retinal detachment (RD) from retinopathy of prematurity (ROP) in the Early Treatment of ROP (ETROP) study.
METHODS
Prospective multi-center non-randomized series of infants with high-risk prethreshold ROP who developed an RD by 6 months corrected age managed with observation or vitreoretinal surgery at investigator discretion.
RESULTS
401 subjects were enrolled in ETROP. RD occurred in 89 eyes of 63 subjects. Follow-up at age 6 years was available for 70 eyes (79%) of 49 subjects. The RDs were stage 4A in 28 eyes (40%), stage 4B in 14(20%), stage 5 in 13(19%), and not classified in 15(21%). The macula was attached in 17 of 50 eyes (34%) following vitrectomy with or without scleral buckle, in 6 of 9(67%) following scleral buckle only, and in 2 of 11 eyes (18%) observed. An attached macula at 6 years of age following vitreoretinal surgery was present in 5 of 16 eyes with stage 4A(31%), 6 of 10 with stage 4B(60%) and 0 of 10 with stage 5.
Favorable visual acuity (> 20/200) was found in 6 of 70 eyes (8.6%); 5 had stage 4A, one not classified. Ten stage 5 eyes underwent vitreoretinal surgery; one retained light perception, 8 were blind and 1 was untestable.
CONCLUSION
Macular attachment was achieved in about one-third of eyes with RD and favorable visual acuity for some eyes with stage 4A. These data confirm the difficulty of obtaining useful vision once ROP has progressed to detachment.
doi:10.1001/archophthalmol.2011.229
PMCID: PMC4416698  PMID: 21911664
5.  Corrugated Waveguide Mode Content Analysis Using Irradiance Moments 
We present a novel, relatively simple method for determining the mode content of the linearly polarized modes of a corrugated waveguide using the moments of the intensity pattern of the field radiated from the end of the waveguide. This irradiance moment method is based on calculating the low-order irradiance moments, using measured intensity profiles only, of the radiated field from the waveguide aperture. Unlike the phase retrieval method, this method does not use or determine the phase distribution at the waveguide aperture. The new method was benchmarked numerically by comparison with sample mode mixtures. The results predict less than ±0.7% error bar in the retrieval of the mode content. The method was also tested using high-resolution experimental data from beams radiated from 63.5 mm and 19 mm corrugated waveguides at 170 and 250 GHz, respectively. The results showed a very good agreement of the mode content retrieved using the irradiance moment method versus the phase retrieval technique. The irradiance moment method is most suitable for cases where the modal power is primarily in the fundamental HE11 mode, with <8% of the power in high-order modes.
doi:10.1109/TPS.2014.2349797
PMCID: PMC4376011  PMID: 25821260
Corrugated waveguide; irradiance moments and phase retrieval; quasi-optical beam; waveguide modes
6.  Acknowledging Individual Responsibility while Emphasizing Social Determinants in Narratives to Promote Obesity-Reducing Public Policy: A Randomized Experiment 
PLoS ONE  2015;10(2):e0117565.
This study tests whether policy narratives designed to increase support for obesity-reducing public policies should explicitly acknowledge individual responsibility while emphasizing social, physical, and economic (social) determinants of obesity. We use a web-based, randomized experiment with a nationally representative sample of American adults (n = 718) to test hypotheses derived from theory and research on narrative persuasion. Respondents exposed to narratives that acknowledged individual responsibility while emphasizing obesity’s social determinants were less likely to engage in counterargument and felt more empathy for the story’s main character than those exposed to a message that did not acknowledge individual responsibility. Counterarguing and affective empathy fully mediated the relationship between message condition and support for policies to reduce rates of obesity. Failure to acknowledge individual responsibility in narratives emphasizing social determinants of obesity may undermine the persuasiveness of policy narratives. Omitting information about individual responsibility, a strongly-held American value, invites the public to engage in counterargument about the narratives and reduces feelings of empathy for a character that experiences the challenges and benefits of social determinants of obesity.
doi:10.1371/journal.pone.0117565
PMCID: PMC4338108  PMID: 25706743
7.  Epistatic and combinatorial effects of pigmentary gene mutations in the domestic pigeon 
Current biology : CB  2014;24(4):459-464.
Understanding the molecular basis of phenotypic diversity is a critical challenge in biology, yet we know little about the mechanistic effects of different mutations and epistatic relationships among loci that contribute to complex traits. Pigmentation genetics offers a powerful model for identifying mutations underlying diversity, and for determining how additional complexity emerges from interactions among loci. Centuries of artificial selection in domestic rock pigeons have cultivated tremendous variation in plumage pigmentation through the combined effects of dozens of loci. The dominance and epistatic hierarchies of key loci governing this diversity are known through classical genetic studies [1-6], but their molecular identities and the mechanisms of their genetic interactions remain unknown. Here we identify protein-coding and cis-regulatory mutations in Tyrp1, Sox10, and Slc45a2 that underlie classical color phenotypes of pigeons, and present a mechanistic explanation of their dominance and epistatic relationships. We also find unanticipated allelic heterogeneity at Tyrp1 and Sox10, indicating that color variants evolved repeatedly though mutations in the same genes. These results demonstrate how a spectrum of coding and regulatory mutations in a small number of genes can interact to generate substantial phenotypic diversity in a classic Darwinian model of evolution [7].
doi:10.1016/j.cub.2014.01.020
PMCID: PMC3990261  PMID: 24508169
8.  Enhanced silencing and stabilization of siRNA polyplexes by histidine-mediated hydrogen bonds 
Biomaterials  2013;35(2):846-855.
Branched peptides containing histidines and lysines (HK) have been shown to be effective carriers for DNA and siRNA. We anticipate that elucidation of the binding mechanism of HK with siRNA will provide greater insight into the self-assembly and delivery of the HK:siRNA polyplex. Non-covalent bonds between histidine residues and nucleic acids may enhance the stability of siRNA polyplexes. We first compared the polyplex biophysical properties of a branched HK with those of branched asparagines-lysine peptide (NK). Consistent with siRNA silencing experiments, gel electrophoresis demonstrated that the HK siRNA polyplex maintained its integrity with prolonged incubation in serum, whereas siRNA in complex with NK was degraded in a time-dependent manner. Isothermal titration calorimetry of various peptides binding to siRNA at pH 7.3 showed that branched polylysine, interacted with siRNA was initially endothermic, whereas branched HK exhibited an exothermic reaction at initial binding. The exothermic interaction indicates formation of non-ionic bonds between histidines and siRNA; purely electrostatic interaction is entropy-driven and endothermic. To investigate the type of non-ionic bond, we studied the protonation state of imidazole rings of a selectively 15N labeled branched HK by heteronuclear single quantum coherence NMR. The peak of Nδ1-H tautomers of imidazole shifted downfield (in the direction of deprotonation) by 0.5 to 1.0 ppm with addition of siRNA, providing direct evidence that histidines formed hydrogen bonds with siRNA at physiological pH. These results establish that histidine-rich peptides form hydrogen bonds with siRNA, thereby enhancing the stability and biological activity of the polyplex in vitro and in vivo.
doi:10.1016/j.biomaterials.2013.10.019
PMCID: PMC3920840  PMID: 24161165
9.  Mode Content Determination of Terahertz Corrugated Waveguides Using Experimentally Measured Radiated Field Patterns 
This work focuses on the accuracy of the mode content measurements in an overmoded corrugated waveguide using measured radiated field patterns. Experimental results were obtained at 250 GHz using a vector network analyzer with over 70 dB of dynamic range. The intensity and phase profiles of the fields radiated from the end of the 19 mm diameter helically tapped brass waveguide were measured on planes at 7, 10, and 13 cm from the waveguide end. The measured fields were back propagated to the waveguide aperture to provide three independent estimates of the field at the waveguide exit aperture. Projecting that field onto the modes of the guide determined the waveguide mode content. The three independent mode content estimates were found to agree with one another to an accuracy of better than ±0.3%. These direct determinations of the mode content were compared with indirect measurements using the experimentally measured amplitude in three planes, with the phase determined by a phase retrieval algorithm. The phase retrieval technique using the planes at 7, 10, and 13 cm yielded a mode content estimate in excellent agreement, within 0.3%, of the direct measurements. Phase retrieval results using planes at 10, 20, and 30 cm were less accurate due to truncation of the measurement in the transverse plane. The reported measurements benefited greatly from a precise mechanical alignment of the scanner with respect to the waveguide axis. These results will help to understand the accuracy of mode content measurements made directly in cold test and indirectly in hot test using the phase retrieval technique.
doi:10.1109/TPS.2012.2190105
PMCID: PMC4175724  PMID: 25264391
Corrugated waveguide; gyrotron; vector network analyzer (VNA); waveguide mode decomposition and phase retrieval
10.  Simple Correctors for Elimination of High-Order Modes in Corrugated Waveguide Transmission Lines 
When using overmoded corrugated waveguide transmission lines for high power applications, it is necessary to control the mode content of the system. Ideally, overmoded corrugated transmission lines operate in the fundamental HE11 mode and provide low losses for long distances. Unwanted higher order modes (HOMs), particularly LP11 and HE12, are often excited in the experimental systems due to practical misalignments in the transmission line system. This paper discusses how the unwanted modes propagate along with the fundamental mode in the transmission line system by formulating an equation that relates the center of power offset and angle of propagation of a beam (for the HE11 and LP11 modes) or the waist size and phase front radius of curvature of a beam (for the HE11 and HE12 modes). By introducing two miter bend correctors into the transmission system—miter bends that have slightly angled or ellipsoidal mirrors—the HOMs can be precisely manipulated in the system. This technique can be used to eliminate small quantities of unwanted modes, thereby creating a nearly pure fundamental mode beam with minimal losses. Examples of these applications are calculated and show the theoretical conversion of up to 10% HOM content into the fundamental HE11 mode with minimal losses.
doi:10.1109/TPS.2013.2288493
PMCID: PMC4109364  PMID: 25067859
Corrugated waveguide; gyrotron; linearly polarized modes; millimeter waves; miter bend; mode conversion; oversized waveguide; transmission line alignment
11.  The Pathogenesis of Epstein-Barr Virus Persistent Infection 
Current opinion in virology  2013;3(3):227-232.
Epstein-Barr virus (EBV) maintains a lifelong infection. According to the germinal center model (GCM), latently infected B cells transit the germinal center (GC) to become resting memory cells. Here, the virus resides quiescently, occasionally reactivating to infect new B cells, completing the cycle of infection. The GCM remains the only model that explains EBV biology and the pathogenesis of lymphoma. Recent work suggests modifications to the model notably that the virus contributes only modestly to the GC process and predictions from mathematical models that quiescence within memory B cells shapes the overall structure of viral infection but is not essential for persistence. Rather, it is the cycle of infection which allows viral persistence at the very low levels observed.
doi:10.1016/j.coviro.2013.04.005
PMCID: PMC3789532  PMID: 23683686
12.  Inflammation and the Host Response to Injury, a Large-Scale Collaborative Project: Patient-Oriented Research Core—Standard Operating Procedures for Clinical Care VII—Guidelines for Antibiotic Administration in Severely Injured Patients 
The Journal of trauma  2008;65(6):1511-1519.
When the clinical decision to treat a critically ill patient with antibiotics has been made, one must attempt to identify the site of infection based on clinical signs and symptoms, laboratory or diagnostic radiology studies. Identification of site requires, examination of patient, inspection of all wounds, chest radiograph, and calculation of clinical pulmonary infection score if ventilated, obtaining blood cultures, urinalysis, and line change if clinical suspicion of central venous catheter (CVC) source. If it is impossible to identify site, obtain cultures from all accessible suspected sites and initiate empiric, broad spectrum antibiotics. If likely site can be identified answer these questions: Is intra-abdominal site suspected? Is pulmonary source of infection suspected? Is skin, skin structure or soft tissue site suspected? If yes, does the patient have clinical signs suspicion for necrotizing soft tissue infection (NSTI)? Is a CVC infection suspected? Risk factors for more complicated infections are discussed and specific antibiotic recommendations are provided for each type and severity of clinical infection. Decision to continue, discontinue and/or alter antibiotic/antimicrobial treatment should be based on the clinical response to treatment, diagnostic or interventional findings, and culture and sensitivity data, bearing in mind that not all patients with infections will have positive cultures because of limitations of specimen handling, microbiology laboratory variations, time between specimen acquisition and culture, or presence of effective antibiotics at the time that specimens were obtained. It should also be noted that not all patients with increased temperature/WBC have an infection. Discontinuation of antibiotics is appropriate if cultures and other diagnostic studies are negative.
doi:10.1097/TA.0b013e318184ee35
PMCID: PMC4004064  PMID: 19077651
Sepsis; Antibiotic; Bacterial; Infection; Empiric treatment; Antimicrobial; Bacteria; Therapy; De-escalation
14.  Coactosin-Like 1 Antagonizes Cofilin to Promote Lamellipodial Protrusion at the Immune Synapse 
PLoS ONE  2014;9(1):e85090.
Actin depolymerizing factor-homology (ADF-H) family proteins regulate actin filament dynamics at multiple cellular locations. Herein, we have investigated the function of the ADF-H family member coactosin-like 1 (COTL1) in the regulation of actin dynamics at the T cell immune synapse (IS). We initially identified COTL1 in a genetic screen to identify novel regulators of T cell activation, and subsequently found that it associates with F-actin and localizes at the IS in response to TCR+CD28 stimulation. Live cell microscopy showed that depletion of COTL1 protein impaired T cell spreading in response to TCR ligation and abrogated lamellipodial protrusion at the T cell – B cell contact site, producing only a band of F-actin. Significantly, re-expression of wild type COTL1, but not a mutant deficient in F-actin binding could rescue these defects. In addition, COTL1 depletion reduced T cell migration. In vitro studies showed that COTL1 and cofilin compete with each other for binding to F-actin, and COTL1 protects F-actin from cofilin-mediated depolymerization. While depletion of cofilin enhanced F-actin assembly and lamellipodial protrusion at the IS, concurrent depletion of both COTL1 and cofilin restored lamellipodia formation. Taken together, our results suggest that COTL1 regulates lamellipodia dynamics in part by protecting F-actin from cofilin-mediated disassembly.
doi:10.1371/journal.pone.0085090
PMCID: PMC3890291  PMID: 24454796
15.  Finding the probability of infection in an SIR network is NP-Hard 
Mathematical biosciences  2012;240(2):77-84.
It is the purpose of this article to review results that have long been known to communications network engineers and have direct application to epidemiology on networks. A common approach in epidemiology is to study the transmission of a disease in a population where each individual is initially susceptible (S), may become infective (I) and then removed or recovered (R) and plays no further epidemiological role. Much of the recent work gives explicit consideration to the network of social interactions or disease-transmitting contacts and attendant probability of transmission for each interacting pair. The state of such a network is an assignment of the values {S, I, R} to its members. Given such a network, an initial state and a particular susceptible individual, we would like to compute their probability of becoming infected in the course of an epidemic. It turns out that this and related problems are NP-hard. In particular, it belongs in a class of problems for which no efficient algorithms for their solution are known. Moreover, finding an efficient algorithm for the solution of any problem in this class would entail a major breakthrough in theoretical computer science.
doi:10.1016/j.mbs.2012.07.002
PMCID: PMC3478503  PMID: 22824138
epidemics; SIR networks; contact network; network reliability; NP-hard
16.  The Cycle of EBV Infection Explains Persistence, the Sizes of the Infected Cell Populations and Which Come under CTL Regulation 
PLoS Pathogens  2013;9(10):e1003685.
Previous analysis of Epstein-Barr virus (EBV) persistent infection has involved biological and immunological studies to identify and quantify infected cell populations and the immune response to them. This led to a biological model whereby EBV infects and activates naive B-cells, which then transit through the germinal center to become resting memory B-cells where the virus resides quiescently. Occasionally the virus reactivates from these memory cells to produce infectious virions. Some of this virus infects new naive B-cells, completing a cycle of infection. What has been lacking is an understanding of the dynamic interactions between these components and how their regulation by the immune response produces the observed pattern of viral persistence. We have recently provided a mathematical analysis of a pathogen which, like EBV, has a cycle of infected stages. In this paper we have developed biologically credible values for all of the parameters governing this model and show that with these values, it successfully recapitulates persistent EBV infection with remarkable accuracy. This includes correctly predicting the observed patterns of cytotoxic T-cell regulation (which and by how much each infected population is regulated by the immune response) and the size of the infected germinal center and memory populations. Furthermore, we find that viral quiescence in the memory compartment dictates the pattern of regulation but is not required for persistence; it is the cycle of infection that explains persistence and provides the stability that allows EBV to persist at extremely low levels. This shifts the focus away from a single infected stage, the memory B-cell, to the whole cycle of infection. We conclude that the mathematical description of the biological model of EBV persistence provides a sound basis for quantitative analysis of viral persistence and provides testable predictions about the nature of EBV-associated diseases and how to curb or prevent them.
Author Summary
Epstein-Barr virus (EBV) is a herpesvirus that establishes a lifelong persistent infection in virtually all human beings. This infection is a risk factor for the subsequent development of certain tumors and possibly also autoimmune diseases. In order to understand the origin of these diseases, it is necessary to first understand how EBV maintains persistent infection. We have used mathematical analysis to study this question. We find that the characteristic cycle of infected stages that EBV establishes in vivo allows it to persist stably at extremely low levels. This represents a consistent mathematical description of EBV infection and allows us to describe what must change to convert benign infection into pathogenic infection, as well as what kind of efficacy drugs and vaccines must have in order to be useful.
doi:10.1371/journal.ppat.1003685
PMCID: PMC3798424  PMID: 24146621
17.  Zonisamide for Weight Loss in Adolescents 
Obesity in children and adolescents is a growing epidemic in the United States, and physicians are increasingly looking for safe and effective treatments. In recent years, pharmacologic treatment has been considered for severe and refractory cases of adolescent obesity. We present a case of an obese adolescent who presented to an inpatient psychiatric unit with a body mass index (BMI) of 37.8 (>98th percentile for age). He was started on zonisamide for the purposes of weight loss, and a steady decrease in weight and BMI was noted through 4 months of outpatient follow-up. During this time, the patient's weight decreased from 126.8 kg to 106.2 kg, a 20.6-kg loss, representing a 16.25% reduction in weight. His most recent BMI decreased to 31.7 (96th percentile for age). We discuss the potential use of zonisamide for weight loss in adolescents, considering the potential risks and benefits.
doi:10.5863/1551-6776-18.4.311
PMCID: PMC3979054  PMID: 24719592
adolescents; antiobesity agents; obesity; weight loss; zonisamide
18.  Genomic diversity and evolution of the head crest in the rock pigeon 
Science (New York, N.Y.)  2013;339(6123):1063-1067.
The geographic origins of breeds and genetic basis of variation within the widely distributed and phenotypically diverse domestic rock pigeon (Columba livia) remain largely unknown. We generated a rock pigeon reference genome and additional genome sequences representing domestic and feral populations. We find evidence for the origins of major breed groups in the Middle East, and contributions from a racing breed to North American feral populations. We identify EphB2 as a strong candidate for the derived head crest phenotype shared by numerous breeds, an important trait in mate selection in many avian species. We also find evidence that this trait evolved just once and spread throughout the species, and that the crest originates early in development by the localized molecular reversal of feather bud polarity.
doi:10.1126/science.1230422
PMCID: PMC3778192  PMID: 23371554
19.  Fluorescein angiography to estimate normal peripheral retinal nonperfusion in children 
Purpose
To estimate the normal distance from vascular termini to ora serrata in children’s eyes.
Methods
Clinical records and peripheral fluorescein angiography images of the ora serrata region, taken using scleral indentation and the RetCam system during examination under anesthesia, were retrospectively reviewed from 33 eyes of 31 consecutive patients with presumed normal peripheral retinal vasculature. All patients had ocular disease either only in the fellow eye or if in the study eye, to a degree judged not likely to affect peripheral retinal vascular development.
Results
The mean age at angiography was 3.8 years (range, 2 months to 13 years). Means of 0.9 disk diameters (DD) of nonperfusion temporally (range, 1.5 DD to 0.5 DD; SD 0.3) and 0.6 DD of nonperfusion nasally (range, 1 DD to 0.25 DD; SD 0.2) were found.
Conclusions
In children up to age 13 years, the avascular retina normally extends 1.5 DD or less temporally and 1.0 DD or less nasally from the ora serrata. Conservatively, ≥2 DD of nonperfusion, 3 standard deviations more than normal, should be considered abnormal and a sign of peripheral nonperfusion. These data may serve as preliminary indicators of the range of normal when evaluating diseases with retinal vascular abnormalities in children.
doi:10.1016/j.jaapos.2011.12.157
PMCID: PMC3756139  PMID: 22681939
20.  A Val85Met Mutation in Melanocortin-1 Receptor Is Associated with Reductions in Eumelanic Pigmentation and Cell Surface Expression in Domestic Rock Pigeons (Columba livia) 
PLoS ONE  2013;8(8):e74475.
Variation in the melanocortin-1 receptor (Mc1r) is associated with pigmentation diversity in wild and domesticated populations of vertebrates, including several species of birds. Among domestic bird species, pigmentation variation in the rock pigeon (Columbalivia) is particularly diverse. To determine the potential contribution of Mc1r variants to pigment diversity in pigeons, we sequenced Mc1r in a wide range of pigeon breeds and identified several single nucleotide polymorphisms, including a variant that codes for an amino acid substitution (Val85Met). In contrast to the association between Val85Met and eumelanism in other avian species, this change was associated with pheomelanism in pigeons. In vitro cAMP accumulation and protein expression assays revealed that Val85Met leads to decreased receptor function and reduced cell surface expression of the mutant protein. The reduced in vitro function is consistent with the observed association with reduced eumelanic pigmentation. Comparative genetic and cellular studies provide important insights about the range of mechanisms underlying diversity among vertebrates, including different phenotypic associations with similar mutations in different species.
doi:10.1371/journal.pone.0074475
PMCID: PMC3744500  PMID: 23977400
21.  Comparison of Traditional Cardiovascular Risk Models and Coronary Atherosclerotic Plaque as Detected by Computed Tomography for Prediction of Acute Coronary Syndrome in Patients With Acute Chest Pain 
Objectives
The objective was to determine the association of four clinical risk scores and coronary plaque burden as detected by computed tomography (CT) with the outcome of acute coronary syndrome (ACS) in patients with acute chest pain. The hypothesis was that the combination of risk scores and plaque burden improved the discriminatory capacity for the diagnosis of ACS.
Methods
The study was a subanalysis of the Rule Out Myocardial Infarction Using Computer-Assisted Tomography (ROMICAT) trial—a prospective observational cohort study. The authors enrolled patients presenting to the emergency department (ED) with a chief complaint of acute chest pain, inconclusive initial evaluation (negative biomarkers, nondiagnostic electrocardiogram [ECG]), and no history of coronary artery disease (CAD). Patients underwent contrast-enhanced 64-multidetector-row cardiac CT and received standard clinical care (serial ECG, cardiac biomarkers, and subsequent diagnostic testing, such as exercise treadmill testing, nuclear stress perfusion imaging, and/or invasive coronary angiography), as deemed clinically appropriate. The clinical providers were blinded to CT results. The chest pain score was calculated and the results were dichotomized to ≥10 (high-risk) and <10 (low-risk). Three risk scores were calculated, Goldman, Sanchis, and Thrombolysis in Myocardial Infarction (TIMI), and each patient was assigned to a low-, intermediate-, or high-risk category. Because of the low number of subjects in the high-risk group, the intermediate- and high-risk groups were combined into one. CT images were evaluated for the presence of plaque in 17 coronary segments. Plaque burden was stratified into none, intermediate, and high (zero, one to four, and more than four segments with plaque). An outcome panel of two physicians (blinded to CT findings) established the primary outcome of ACS (defined as either an acute myocardial infarction or unstable angina) during the index hospitalization (from the presentation to the ED to the discharge from the hospital). Logistic regression modeling was performed to examine the association of risk scores and coronary plaque burden to the outcome of ACS. Unadjusted models were individually fitted for the coronary plaque burden and for Goldman, Sanchis, TIMI, and chest pain scores. In adjusted analyses, the authors tested whether the association between risk scores and ACS persisted after controlling for the coronary plaque burden. The prognostic discriminatory capacity of the risk scores and plaque burden for ACS was assessed using c-statistics. The differences in area under the receiver-operating characteristic curve (AUC) and c-statistics were tested by performing the −2 log likelihood ratio test of nested models. A p value <0.05 was considered statistically significant.
Results
Among 368 subjects, 31 (8%) subjects were diagnosed with ACS. Goldman (AUC = 0.61), Sanchis (AUC = 0.71), and TIMI (AUC = 0.63) had modest discriminatory capacity for the diagnosis of ACS. Plaque burden was the strongest predictor of ACS (AUC = 0.86; p < 0.05 for all comparisons with individual risk scores). The combination of plaque burden and risk scores improved prediction of ACS (plaque + Goldman AUC = 0.88, plaque + Sanchis AUC = 0.90, plaque + TIMI AUC = 0.88; p < 0.01 for all comparisons with coronary plaque burden alone).
Conclusions
Risk scores (Goldman, Sanchis, TIMI) have modest discriminatory capacity and coronary plaque burden has good discriminatory capacity for the diagnosis of ACS in patients with acute chest pain. The combined information of risk scores and plaque burden significantly improves the discriminatory capacity for the diagnosis of ACS.
doi:10.1111/j.1553-2712.2012.01417.x
PMCID: PMC3424404  PMID: 22849339
22.  Low-Loss Transmission Lines for High-Power Terahertz Radiation 
Applications of high-power Terahertz (THz) sources require low-loss transmission lines to minimize loss, prevent overheating and preserve the purity of the transmission mode. Concepts for THz transmission lines are reviewed with special emphasis on overmoded, metallic, corrugated transmission lines. Using the fundamental HE11 mode, these transmission lines have been successfully implemented with very low-loss at high average power levels on plasma heating experiments and THz dynamic nuclear polarization (DNP) nuclear magnetic resonance (NMR) experiments. Loss in these lines occurs directly, due to ohmic loss in the fundamental mode, and indirectly, due to mode conversion into high order modes whose ohmic loss increases as the square of the mode index. An analytic expression is derived for ohmic loss in the modes of a corrugated, metallic waveguide, including loss on both the waveguide inner surfaces and grooves. Simulations of loss with the numerical code HFSS are in good agreement with the analytic expression. Experimental tests were conducted to determine the loss of the HE11 mode in a 19 mm diameter, helically-tapped, three meter long brass waveguide with a design frequency of 330 GHz. The measured loss at 250 GHz was 0.029 ± 0.009 dB/m using a vector network analyzer approach and 0.047 ± 0.01 dB/m using a radiometer. The experimental results are in reasonable agreement with theory. These values of loss, amounting to about 1% or less per meter, are acceptable for the DNP NMR application. Loss in a practical transmission line may be much higher than the loss calculated for the HE11 mode due to mode conversion to higher order modes caused by waveguide imperfections or miter bends.
doi:10.1007/s10762-012-9870-5
PMCID: PMC3498493  PMID: 23162673
Terahertz; High power; Transmission line; Waveguide; Gyrotron
23.  TREATING UVEITIS-ASSOCIATED HYPOTONY WITH PARS PLANA VITRECTOMY AND SILICONE OIL INJECTION 
Retina (Philadelphia, Pa.)  2010;30(1):140-145.
Purpose
The purpose of this study was to determine the effect on intraocular pressure (IOP) and visual acuity of treating uveitis-related hypotony in patients with vitrectomy and intravitreal silicone oil injection.
Methods
Patients who underwent pars plana vitrectomy and silicone oil injection for uveitis-associated hypotony treatment were identified retrospectively. The primary outcome was maintaining an IOP of ≥5 mmHg. Visual acuity improvement was defined as an increase in ≥2 lines of acuity.
Results
Twelve eyes of 10 patients were identified. Median preoperative IOP was 2 mmHg (range: 0–7 mmHg). Two of 12 eyes had an IOP of ≥5 mmHg at presentation. The number of eyes with an IOP of ≥5 mmHg was 7 of 12 eyes (58%) at 1 month, 4 of 12 eyes (33%) at 3 months, 6 of 12 eyes (50%) at 6 months, and 3 of 9 eyes (33%) at 1 year. Five of 12 eyes (42%) were reinjected between 1 and 3 times with silicone oil for recurring hypotony. Median presenting Snellen visual acuity was counting fingers (range: 20/125 to light perception). Seven of 9 eyes (78%) maintained their preoperative vision at 1 year.
Conclusion
Intraocular pressure elevated modestly in most patients in this series. However, results were often transient, and some eyes required repeated silicone oil injections. Although silicone oil is reasonable to consider for the treatment and maintenance of IOP in patients with ocular hypotony secondary to uveitis, better treatments are needed.
doi:10.1097/IAE.0b013e3181b32f06
PMCID: PMC3695593  PMID: 19823108
hypotony; silicone oil; uveitis
24.  Continuous-Wave Operation of a Frequency-Tunable 460-GHz Second-Harmonic Gyrotron for Enhanced Nuclear Magnetic Resonance 
The design, operation, and characterization of a continuous-wave (CW) tunable second-harmonic 460-GHz gyrotron are reported. The gyrotron is intended to be used as a submillimeter-wave source for 700-MHz nuclear magnetic resonance experiments with sensitivity enhanced by dynamic nuclear polarization. The gyrotron operates in the whispering-gallery mode TE11,2 and has generated 16 W of output power with a 13-kV 100-mA electron beam. The start oscillation current measured over a range of magnetic field values is in good agreement with theoretical start currents obtained from linear theory for successive high-order axial modes TE11,2,q. The minimum start current is 27 mA. Power and frequency tuning measurements as a function of the electron cyclotron frequency have also been carried out. A smooth frequency tuning range of 1 GHz was obtained for the operating second-harmonic mode either by magnetic field tuning or beam voltage tuning. Long-term CW operation was evaluated during an uninterrupted period of 48 h, where the gyrotron output power and frequency were kept stable to within ±0.7% and ±6 ppm, respectively, by a computerized control system. Proper operation of an internal quasi-optical mode converter implemented to transform the operating whispering-gallery mode to a Gaussian-like beam was also verified. Based on the images of the gyrotron output beam taken with a pyroelectric camera, the Gaussian-like mode content of the output beam was computed to be 92% with an ellipticity of 12%.
PMCID: PMC3677787  PMID: 23761938
Dynamic nuclear polarization (DNP); nuclear magnetic resonance (NMR); second cyclotron harmonic; submillimeter wave; terahertz; tunable gyrotron
25.  Incremental Diagnostic Value of Regional Left Ventricular Function Over Coronary Assessment by Cardiac Computed Tomography for the Detection of Acute Coronary Syndrome in Patients with Acute Chest Pain – From The ROMICAT Trial 
Background
The incremental value of regional left ventricular function (LVF) over coronary assessment to detect acute coronary syndrome (ACS) is uncertain.
Methods and Results
We analyzed 356 patients (mean age 53±12 years, 62% male) with acute chest pain and inconclusive initial ED evaluation. Patients underwent 64-slice contrast-enhanced cardiac CT prior to hospital admission. Caregivers and patients remained blinded to the results. Regional LVF and presence of coronary atherosclerotic plaque and significant stenosis (>50%) were separately assessed by two independent readers. Incremental value of regional LVF to predict ACS was determined in the entire cohort and in subgroups of patients with nonobstructive CAD, inconclusive assessment for stenosis (defined as inability to exclude significant stenosis due to calcium or motion), and significant stenosis. During their index hospitalization, 31 patients were ultimately diagnosed with ACS (8 myocardial infarction, 22 unstable angina), of which 74% (23 patients) had regional LV dysfunction. Adding regional LVF resulted in a 10% increase in sensitivity to detect ACS by cardiac CT (87%, 95%-confidence interval [CI]: 70–96%) and significantly improved the overall accuracy (c-statistic: 0.88 vs. 0.94 and 0.79 vs. 0.88, for extent of plaque and presence of stenosis; respectively; both p<0.03). The diagnostic accuracy of regional LVF for detection of ACS has 89% sensitivity and 86% specificity in patients with significant stenosis (n=33) and 60% sensitivity and 86% specificity in patients with inconclusive coronary CTA (n=33).
Conclusions
Regional LVF assessment at rest improves diagnostic accuracy for ACS in patients with acute chest pain, especially in those with coronary artery disease and thus may be helpful to guide further management in patients at intermediate risk for ACS.
Clinical Trial Registration
URL: http://clinicaltrials.gov/ct2/show/NCT00990262. Unique Identifier: NCT00990262
doi:10.1161/CIRCIMAGING.109.892638
PMCID: PMC3662235  PMID: 20484542
computed tomography; left ventricular function; acute coronary syndrome; emergency department

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